-desoxy-



United States Patent 3,093,648 18,8-DESOXY-18-OXO- AND 1.8-OX1MINO-RESERPATES vMichael Mullen Robison, Berkeley Heights, Harold BeldingMacPhillamy, Madison, and Robert Armistead Lucas, Mendh'am, N .J.,assignors to Ciba Corporation,

a corporation of Delaware No Drawing. Ih'led July 31, 1961, Ser. No.127,853 12 Claims. (Cl. 260-287) The present invention concerns3-epi-allo-yohimban-l8- one compounds having the nucleus of the formula:

More particularly, it relates to 3-epi-allo-yohimban-18-one16,8-carbcxy-lic acid esters, particularlyl7a-R-3-epiaalloyohimban-lS-one l6fl-carboxylic acid esters, in which Rrepresents primarily lower alkoxy, as well as cyano, the functionalketone derivatives of such compounds, as well as the salts, N-oX-ides orsalts of N oxides thereof. Apart from the groups in the l6B-position andthe Not-position, and the oxo-group in the l8-position, the compounds ofthe present invention may contain additional substituehts. T-hus,substituents attached to the positions of the aromatic nucleus, i.e.ring A, of the molecule, more specifically to the 9-position, thelO-position, the ll-position and/or the IZ positi-on, are represented,for example, by aliphatic hydrocarbon, such as lower alkyl and the like,etherified hydroxyl, particularly lower alkoxy, as well ascycloalkyloxy, cycloalkyl-lower valkoxy, carbocyclic aryloxy,carbocyclic aryl-lower alkoxy, lower alkylenedioxy and the like,esterified hydroxyl, particularly halo-gene, as well as loweralkoxy-carbonyloxy, lower alkanoyloxy and the like, etherified mercapto,such as lower alkylmercapto and the like, nitro, amino, such asN,N-disubstituted amino and the like, halogeno lower alkyl, particularly:trifluoromethyl, or any other suit-able subs'tituent. Othersubstituents, particularly aliphatic hydrocarbon radicals, such as loweralkyl, may also be attached to positions available for sub stitution inother nuclei, particularly of the heterocyclic nucleus C, morespecifically to the S-positiori and/or the 6-position.

More especially, the invention is directed to compounds of the formula:

in which R represents an aliphatic radical, primarily lower alkyl, aswell as a substituted aliphatic radical, primarily substituted loweralkyl, such as, for example, monocyc'lic carbocyclic aryl-lower alkyl,e-g. phenyl-lower alkyl and the like, etherified hydroxy-lower alkyl,e.g. lower 3,093,648 Patented June 11, 1963 alkoxy-lower alkyl and thelike, tertiary amino lower alkyl, e.-g. N,N-di-lower alkyl-amino-loweralkyl and the like, R2 stands primarily for lower alkoxy, as well as forcyano, each of the radicals R R and R stands for hydrogen, loweraliphatic hydrocarbon, particularly lower alkyl, substituted aliphatichydrocarbon, particularly substituted lower alkyl, such ashalogeno-lower alkyl, especially trifluoromethyl, etherified hydroxyl,particularly lower alkoxy, as well as cycloalkyloxy, cycloalkyl-loweralkoxy, carbocyclic aryloxy, carbocyclic laryblower alkoXy or any otheranalogous etherified hydroxyl group, esterified hydroxyl, particularlyhalogeno, as well as lower :alkoXy-carbonyloxy, lower alkanoyloxy andthe like, etherified mercapt-o, particularly lower alkyl-mercapto,nitro, amino, e.g. N,N-di-substituted amino and the like, or, whenevertwo of the groups R R and R are attached to two adjacent positions andare taken together, for lower alkylenedioxy, and R attached to one ofthe positions 5 and 6, stands for hydrogen or lower alkyl, or thefunctional ketone derivatives of such compounds, or the salts, N-oxidesor salts of N-oxides thereof, as well as process for the preparation ofsuch compounds. I

The aliphatic radical of the alcohol portion of the ester groupingattached to the Mir-position of the molecule, which, in the aboveformula, is represented by the group R stands above all for lower alkylhaving from one to ten, preferably from one to four, carbon atoms; suchgroups are particularly methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secondary butyl and the like, as 'well was n-pentyl,isopentyl, n-hexyl, n-heptyl and the like.

The esteri-fy-ing portion of the ester grouping attached to theMIR-position of the molecule, represented by the radical R in the aboveformula, may also stand for a substituted aliphatic radical,particularly substituted lower alkyl, such as, for example, monocycliccarbocyclic aryllower alkyl, in which lower alkyl has from one to fourcarbon atoms, such as phenyl-lower alkyl, eg. benzyl, l phenyl-ethyl, Zphenylethyl and the like, or phenyl-lower alkyl, in which phenyl issubstituted by lower alkyl, e.-g. methyl, ethyl and the like, loweralkoxy, e.g. rnethoxy, ethoxy and the like, halogeno, erg. fiuor-o,chloro, broino and the like, or any other Suitable substituent.

Other substituted aliphatic, particularly lower alkyl radicals, asrepresented by the group R in the above formula, are aliphatic,particularly "lower alkyl, radicals substituted by functional groups,such as etherified hydroxyl, particularly lower alkoxy having preferably[from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy,isopropylox y, n-butyloxy and the like, tertiary amino, such asN,N-di-lower alkyl-amino, in which lower alkyl has [from one to tourcarbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methylamino,N,N-diethylamino, N,N- di-n-propylamin-o, N,N-di-isopropyl;amino and thelike, as well as 1-N,N-alkylene-imino, in which alkylene has from fourto-six ring carbon atoms, e.g. l-pyrrolidino, l-piperidino,1-N,N-hexamethyleneimino and the like, l-N,N-oxaalkylene-imino, in whichoX-a-alkylene has preferably four ring carbon atoms, erg. 4-rnorpholinoand the like, l-N,N- thia-alkylene-i-mino, in which alkylene haspreferably four ring carbon atoms, e.g. 41thiomorp'ho1ino and the like,or l-N,N-1ower aza-alkylene-imino, in which aza-alkylene has from fourto six ring carbon atoms, particularly 4- lower alkyl-l-piperazino, e.g.4-methyl-1-piperazino, 4'- ethyl-l-piperazino and the like. Thealiphatic, particularly lower alkyl, portion in an aliphatic, especiallylower alkyl, radical substituted by functional groups, as represented,for example, by etherified hydroXydowe-r alkyl, tertiary amino-loweralkyl and the like, is represented by a lower alkylene radical, whichhas from two to four carbon atoms separating the functional group, suchas etherified hydroxyl, tertiary amino and the like, from the16p-carboxyl group by at least two carbon atoms. Preferably, such loweralkylene radical has from two to three carbon atoms separating thesubstituent from the l6 8-carboxyl group by the same number of carbonatoms. Such alkyl- .ene radicals are primarily 1,2-ethylene,l-methyl-l,2-ethylene, 2-methyl-l,2-ethylene, 1,3-propylene and thelike, as well as 1,4-butylene and the like. Aliphatic, particularlylower alkyl, radicals containing a functional group, as represented by Rin the above formulae, may be, for example, 2-lower alkoxy-ethyl, e.g.Z-methoxyethyl, 2-

ethoxyethyl and the like, 2-lower alkoxy-propyl, e.g. 2-

sented by thegroup R in the above formula, stands for lower alkoxy whichhas preferably from one to four carbon atoms, such as ethoxy,n-propyloxy, isopropyloxy, n-butyloxy, ,isobutyloxy and the like, butabove all methoxy. It may also represent cyano.

Substituents attached to any of the positions available for substitutionin ring A, particularly those represented by the groups R R and R (eachof which may also stand for hydrogen) in the previously given formula,may be, for example, lower aliphatic hydrocarbon, especially loweralkyl, having preferably from one to four carbon atoms, e.g methyl,ethyl, n-propyl, isopropyl, n-butyl and the like, or functional groups,such as, for example, etherified hydroxyl, particularly lower alkoxy,having preferably from one to four carbon atoms, e.g. methoxy, ethoxy,n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, as wellas cycloalkyloxy, in which cycloalkyl has from three to eight,preferably from five to six, ring carbon atoms, e.g. cyclopentyloxy,cyclohexyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkylhas from three to eight, preferably from five to six, ring carbon atoms,e.g. cyclopentylmethoxy, 2-cyclopentylethoxy, cyclohexylmethoxy and thelike, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g.phenyloxy and the like, carbocyclic aryl-lower alkoxy, such asmonocyclic carbocyclic 'aryl-lower alkoxy, for example, phenylloweralkoxy, e.g. benzyloxy, diphenylmethoxy, 2-phenylethoxy and the like,esterified hydroxyl, particularly halogeno (representing hydroxylesterified by a hydrohalic acid), particularly halogeno having an atomicweight of 19 to 80, e.g. fluoro, chloro or bromo, and the like, as wellas lower alkoxy-carbonyloxy, e.g, methoxycarbonyloxy, ethoxycarbonyloxyand the like, or lower alk-anoyL oxy, e.g. acetoxypropionyloxy and thelike, etherified mercapto, particularly lower alkyl-mercapto, havingpreferably from one to four carbon atom-s, e.g. methylrnercapto,ethylmercapto and the like, nitro, amino, pantieularlyN,N-di-substituted amino, such as N,N-di-lower alkyl-amino, e.g.N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino and the like,halogeno-lower alkyl, particularly trifluoromethyl and [the like, or anyother suitable functional group. A substituent may also be attached totwo adjacent positions of ring A and form a fused-on ring; for example,two of the radicals R R and R in the formula, when substituting twoneighboring positions and taken together, may also form a fused-oncyclic substituent. Such substituents may be represented, for example,by lower alkylene-dioxy, e.g. methylenedioxy, 1,1-ethylenedioxy and thelike, or any other analogous grouping.

Substituents, which may be attached to other positions in the molecule,particularly to positions available for substitution in ring C, areprimarily aliphatic hydrocarbon, such as lower alkyl, having preferablyfrom one to four carbon atoms, particularly methyl, as well as ethyl,npropyl, isopropyl and the like. The radical R in the previously givenformula, which stands primarily for hydrogen, may, therefore, alsorepresent lower alkyl, particularly methyl, as well as ethyl and thelike.

Also included within the scope of the present invention are thefunctional ketonic derivatives of the 3-epiallo-ychimban-lS-onel6/3-carboxylic acid esters. Such derivatives are, for example, theketals with lower alkylene glycols, e.g. ethylene glycols, 1,2-propyleneglycol and the like, mercapto lower alkanols, e.g. Z-mercapto-ethanoland the like, or with lower alkane di-thiols, e.g. 1,2-ethane di thioland the like. Other derivatives are nitrogenous ketonic derivatives,such as oximes, carbazones, thiocarbazones and the like, as well ashydrazones, such as the 2,4-dinitro-phenyl-hydrazones and the like.

Salts of the compounds of this invention, including those of thefunctional ketonic derivatives thereof, are acid addition salts,primarily the pharmacologically and therapeutically acceptable,non-toxic acid addition salts with inorganic acids, e.g. hydrochloric,hydrobromic, sulfuric, phosphoric acids and the like, or with organicacids, such as organic carboxylic acids, e.g. acetic, tartaric, citric,succinic, maleic acid and the like, or with organic sulfonic acids, e.g.methane sulfonic, ethane sulfonic, 2- hydroxy-ethane sulfonic, ethane1,2-disulfonic acid and the like.

Also included within the scope of the present invention are the N-oxidesof the above-mentioned compounds, as well as the acid addition salts,particularly the pharmacologically and therapeutically non-toxic acidaddition salts of these N-oxides, such as the addition salts with theabove-mentioned inorganic and organic acids.

In view of the fact that several asymmetric carbon atoms are present inthe compounds of this invention, the latter may be obtained in the formof a mixture of racemates, racemates or optically pure compounds.

The compounds of the present invention have sedative and tranquilizingeffects on the central nervous system, as well as antihypertensiveproperties. However, compared with the antihypertensive and sedativeeffects exerted by the naturally occurring Rauwolfia alkaloids, such as,for example, reserpine, deserpidine, rescinnamine and the like, thecompounds of this invention appear to have more predominant sedativeeffects with negligible antihypertensive activities.

Furthermore, it has also been found that the compounds of this inventionact quickly, and the activity is of definite duration, thus making therecovery after treatment more complete and easily controllable. It hasalso been found that the acid addition salts of these compounds arewatersoluble substances, and are, therefore, extremely useful in thepreparation of pharmaceutical compositions, particularly of aqueoussolutions for injection and aqueous oral preparations, e.g. elixirs andthe like.

The compounds of the present invention are, therefore, primarily used assedative and tranquilizing agents to relieve states of hyperactivity,tension and agitation, as, for example, associated with mentaldisturbances, anxiety and the like. They may also be used asanrtihypertensive agents to counteract hypertensive conditions, such asrenal hypertension and the like. Furthermore, the compounds of thisinvention are useful in calming laboratory test animals, such asmonkeys, dogs, cats and the like, as well as in the veterinary field toquiet animals, particularly chickens, turkeys and the like, as Well asother domestic animals to facilitate handling during vaccination,shipment and the like.

The compounds of this invention may be used in the form ofpharmaceutical preparations, which contain the new compounds inadmixture with a pharmaceutical organic or inorganic, solid or liquidcarrier suitable for enteral or parenteral administration. For making upthe preparations there can be employed substances which do not reactwith the new compounds, such as water, gelatine, lactose, starches,stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils,benzyl alcohols, gums, propylene glycol, polyalkylene glycols or anyother known carrier used in the manufacture of pharmaceuticalpreparations. The latter may be in solid form, for example, as capsules,tablets, dragees, and the like, or in liquid form, for example, assolutions, suspensions and the like emulsions. If desired, they maycontain auxiliary substances such as preserving, stabilizing, wet: ting,emulsifying agents and the like, as well as salts for varying theosmotic pressure, buffers, etc. They may also contain, in combination,other useful substances.

The compounds of the present invention may also serve as intermediatesfor the preparation of other useful compounds. For example, upontreatment with a reducing reagent, a 3-epi-allo-yohimban-18-one16B-carboxylic acid ester may be converted into correspondingl8-hydroxy-3-epi-allo-yohimbane 16/3-carboxylic acid esters. Thus,reduction with sodium borohydride affords the formation of a mixture ofan ISB-hydroxy-B-epi-allm yohimbane 16/3-carboxylic acid ester and an18a-hydroxy- 3-epi-allo-yohimbane 16fi-carboxylic acid ester, which maybe separated into the two single compounds.

The two resulting monoesters may serve as intermediates. For example, an18a-hydroxy-3-epi-allo-yohimbane 16,8-carboxylic acid ester may beconverted into an 18wsulfonyloxy-3-epi-allo-yohimbane 16,6-carboxylicacid ester, such as an 18a-(4-bromophenyl-sulfonyloxy)-3-epi-all-o-yohimbane l6fi-carboxylic acid ester, and the like. Thelatter may then be subjected to alcoholysis, for example, to treatmentwith a lower alkanol, if desired, in the presence of a tertiary organicamine, eg

N,N,N-triethylamine, pyridine and the like, and converted into anISfl-etherified hydroxy-3-epi-allo-yohimbane l6B-carboxylic acid ester,which compounds have pronounced sedative and tranquilizing propertiesand can be used as sedative and tranquilizing agents. The other type ofmonoesters, ie the 18fl-hydroxy-3-epi-alloyohimbane lfifi-carboxylicacid esters are known compounds and are used as intermediates, forexample, in the preparation of 18,8-esterified hydroxy 3-epi-alloyohimbane l6fi-carboxylic acid esters.

The 3-epi-allo-yohimban-l8-one 16p-carboxylic acid esters of thisinvention may, therefore, be used as important intermediates in thetransformation of one configuration of the 18-substituent into theother. For example, by starting with one of the known 185-hydroxy-3-epi-allo-yohimbane 16,8-carboxylic acid esters, esterifying the latterby treatment with a reactive derivative of a strong organic sulfonicacid, e.g. 4-bromo-benzene sulfonyl chloride and the like, oxidizing theresulting ester as will be shown hereinbelow to the3-epi-allo-yohimbanl8-one 16fl-carboxylic acid ester, reducing thelatter to form the mixture of an 18et-hydroxy-3-epi-allo-yohimbane l68-car-boxylic acid ester and an l8B-hydroxy-3-epi-allo yohimbanel6/3-carboxylic acid ester, which mixture can be separated into thesingle components and isolating the 18a-hydroxy-3-epi-allo-yohimbaneIGB-carb-oxylic acid ester, an epimerization at the lS-position has beenachieved and the resulting compound can be used for further usefulpurposes.

Apart from having shown sedative and tranquilizing properties, thefunctional ketonic derivatives are also useful as intermediates, forexample, in any purification procedure involving the free3-epi-allo-yohimban-18-one. l6B-carboxylic acid esters, into which theycan be con-: verted according to known methods.

A preferred group of compounds having the aboveim i ll t OCH;

and the corresponding oximes of such compounds having the formula:

in which formulae R represents lower alkyl, having preferably from oneto four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secondary butyl and the like, and R represents lower alkoxyhaving from one to four carbon atoms, particularly methox'y, as well asethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R ispreferably attached to the 10-position or the ll-position, and thepharmacologically and therapeutically acceptable, nontoxic acid additionsalts of such compounds.

The compounds of the present invention may be pre-' pared, for example,by treating an 18-.reactive esterified hydroxy-3-epi-allo-yohimbane l63-carboxylic acid ester, particularly a compound having one of theformulae:

and

in which R R R R R and R have the previously given meaning, and Erepresents a reactive esterified hydroxyl group, or a salt, an N-oxideor a salt of an N-oxide thereof, with a sulfoxide oxidation reagent,and, if desired, converting a resulting salt into a free compound,and/or, if desired, converting a resulting compound into a functionalketonic derivative or a salt, an N-oxide or a salt of an N-oxide of suchcompounds, and/or, if desired, converting in a resulting compound the16fi-carboxylic acid ester group into another carboxylic acid estergroup, and/or, if desired, separating a mixture of isomers into thesingle isomers.

The reactive esterified hydroxyl group in the 18-position of thestarting material is represented by a hydroxyl group esterified by astrong inorganic acid, particularly a hydrohalic acid, e.g.hydrochloric, hydrobrornic, hydriodic acid and the like. More especiallya reactive esterified hydroxyl group is esterified with a strong organicsulfonic acid, such as a lower alkane sulfonic acid, e.g. methanesulfonic, ethane sulfonic acid and the like, a hydroxylower alkanesulfonic acid, e.g. Z-hydroxy-ethane sulfonic acid and the like, or,more particularly, with a carbocyclic aryl sulfonic acid, such as amonocyclic carbocyclic aryl sulfonic acid, for example, benzene sulfonicacid, halogeno-benzene sulfonic acid, e.g. 4-bromo-benzene sulfonic acidand the like, nitro-benzene sulfonic acid, e.g. 3-nitro-benzenesulfonic, 4-nitro-benzene sulfonic acid and the like, loweralkyl-benzene sulfonic acid, e.g. p-toluene sulfonic acid and the like,or any other suitable strong inorganic or organic, particularly organicsulfonic acid. The reactive esterified hydroxyl group, for example, thegroup E in the above formulae, may, therefore, be represented byhalogeno, (i.e. a hydroxyl group esterified by a hydrohalic acid) e.g.chloro, bromo, iodo and the like, lower alkyl-sulfonyloxy, e.g.methyl-sulfonyloxy, ethyl-sulfonyloxy and the like, hydroxy-loweralkylsulfonyloxy, e.g. 2-hydroxy-ethyl-sulfonyloxy and the like, or,more especially, phenyl-sulfonyloxy, (halogeno-phenyl)-sulfonyloxy, e.g.4bromo-phenyl-sulfonyloxy and the like, (nitro-phenyl)-sulfonyloxy, e.g.3-nitro-phenyl-sulfonyloxy, 4-nitro-phenyl-sulfonyloxy and the like,(lower alkyl-phenyl)-sulfonyloxy, e.g. p-tolyl-sulfonyloxy and the like,or any other suitable reactive esterified hydroxyl group.

The oxidation procedure is carried out by treating the starting materialwith the sulfoxide oxidation reagent, especially with a di-lower alkylsulfoxide. Dimethyl sulfoxide is the reagent of choice; diethylsulfoxide and the like may also be used as a reagent. These reagents arepreferably used in the presence of a mild base, such as, for example, anorganic base, such as an N,N,N-tri-lower alkyl-amine, e.g.N,N,N-triethylamine, and the like, or any other suitable organic base,as well as an inorganic base, such as an alkali metal carbonate, e.g.sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodiumcarbonate, potassium carbonate and the like, or any other suitableinorganic base. The reaction may be performed in the absence of asolvent; an inert solvent, such as, for example, acetonitrile, benzeneand the like, may be added to ensure complete solution. The conversionof the starting material into the S-epi-allo-yohirnban-18-one compoundproceeds preferably at an elevated temperature, if necessary, in aclosed vessel, and/ or in the atmosphere of an inert gas, e.g. nitrogenand the like.

The starting materials used in the above reaction are known or may beprepared according to known procedures. Esters with strong sulfonicacids may be prepared, for example, by esterifying the free l8-hydroxylgroup in an l8-hydroxy-3-epi-allo-yohimbane 16B-carboxylic acid ester,for example, by treatment with a reactive derivative of a strong organicsulfonic acid, such as a halide, particularly a chloride of such acid,in the presence of a base, especially pyridine and the like. Thestarting materials, in which the 18-esterified hyroxyl group has thea-configuration may be obtained, for example, by hydrolyzing anl8,8-sulfonyloxy-3-epi-allo-yohimbane 16/3-carboxylic acid ester(manufactured from an l8B-hydroxy-3-epi-alloyohimbane 16(3-carboxylicacid ester) with water, if desired, in the presence of a tertiaryorganic amine, e.g. N,N,N-triethylamine and the like, and esterifying aresulting 18u-hydroxy-3-epi-allo-yohimbane l6fi-carboxylic in which R RR R R and R have the above-given meaning, or a functional ketonicderivative of such compound, or a salt, an N-oxide or a salt of anN-oxide thereof, by treatment with an acid and isolating the desired3-epi-allo-yohimban-l8-one 16,6-carboxylic acid ester, particularly adesired compound of the formula:

N N H in which R R R R R and R have the previously given meaning, or afunctional ketonic derivative of such compound, or a salt, an N-oxide ora salt of an N-oxide thereof, and, if desired, carrying out the optionalsteps.

Acids used in the above isomerization procedure are, for example,organic carboxylic acids, particularly aliphatic hydrocarbon carboxylicacids, such as lower alkanoic acids, e.g. acetic, propionic acid and thelike, primarily glacial acetic acid, organic sulfonic acids,particularly monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluenesulfonic acid and the like, as well as lower alkane sulfonic acids, e.g.methane sulfonic acid and the like, or strong mineral acids, such ashydrohalic acids, e.g. hydrochloric acid and the like, or mixtures ofacids. The reaction may be carried out in the presence or absence of anadditional solvent; for example, p-toluene sulfonic acid may also beused in the presence of an organic base, e.g. collidine and the like,Whereas hydrogen chloride may be used in an anhydrous lower alkanol,e.g. methanol, ethanol and the like. Isomerization may occur at roomtemperature or preferably at an elevated temperature, in an open vesselor under pressure, preferably in an atmosphere of nitrogen.

Optimum yields in the isomerization reaction may be obtained by removingthe desired product from the reaction milieu, thus displacing thereaction equilibrium in favor of the product. The removal may beaccomplished by separating the product, if desired, in the form of asalt thereof, from the starting material by exploiting the differentrelative solubilities in different solvent systems. For example, theproduct or a salt thereof may be separated from the starting material ora salt thereof either by adsorption on a suitable material, such asalumina, paper and the like, and subsequent fractional elution, or byfractional crystallization from a solvent or a mixture of solvents. Thestarting material separated from the desired product may then berecycled into the isomerization process, to enhance the overall yield ofthe procedure.

The starting materials used in the isomerization procedure may beproduced, for example, by treatment of an l8-reactive estcrifiedhydroxy-alloyohimbane IGB-carboxylic acid ester, a salt, an N-oxide or asalt of an N-oxide thereof, with a sulfoxide oxidation reagent; thisreaction is carried out according to the method described hereinbefore.

"lhe compounds resulting from the above-outlined procedures may beobtained in the form of an acid addition salt thereof. Such salt may beconverted into the free base, for example, by reacting the former withan alkaline reagent, such as, for example, aqueous ammonia, silver oxideand the like, or an ion exchange resin, or any other suitable alkalinereagent.

Resulting compounds may be converted into a functional ketonicderivative thereof. For example, nitrogenous ketone derivatives,particularly the oximes, as well as the hydrazones, semicarbazones,thiosemicarbazones and the like, may be prepared by treating theresulting ketone compound with the reagent or a salt thereof, especiallywith hydroxylaimine or a salt, such as the hydrochloride, sulfate andthe like, thereof, as well as with a hydrazine, a semicarbazide, athiosemicarbazide and the like, or a salt thereof. The reaction ispreferably carried out while heating in the presence of an inert solventand of an acid neutralizing reagent, e.g. sodium carbonate and the like,particularly whenever an acid addition salt of a reagent is used, and/ora bufier, eg sodium acetate and the like, and/or in the atmosphere of aninert gas, e.g. nitrogen. Other ketone derivatives, such as the ketals,are prepared by reacting the resulting ketone compound with the reagent,such as ethylene glycol and the like, in the presence of a catalyticamount of a suitable acid, e.g. toluene sul-fonic acid and the like.

The compounds of this invention, their ketone derivatives and N-oxidesthereof maybe converted into the salts thereof, for example, by treatinga solution of the free base in a suitable solvent, with the acid or asolution thereof and isolating the resulting salt. Resulting salts maybe converted into other salts, for example, by reacting the former witha metal, such as an alkali metal, eg sodium, potassium and the like,salt or any equivalent salt of an inorganic or organic acid andisolating the desired converted salt. The salts may also be obtained asthe hemihydrates, monohydrates, sesquihydrates or polyhydrates dependingon the conditions used in the formation of the salts.

N-ox ides of the compounds of the present invention may be formedaccording to known methods; for example, a resulting compound,preferably a solution thereof in an inert solvent, may be reacted withan N-oxidizing reagent, such as, for example, hydrogen per-oxide, ozone,persulfuric acid, or more especially, an organic peracid, such as anorganic percarboxyli-c acid, e.g. persulfonic acid, e.g. p-toluenepersulfonic acid and the like. In the N-oxidation reaction an excess ofthe oxidation reagent and/or an increase in temperature should beavoided in order to prevent oxidative degradation.

In a resulting compound, a lfi-esterified carboxyl group may beconverted into another IGB-esterified carboxyl group. This may beachieved according to known methods, for example, bytransesterification.

The transesterification reaction may be carried out, for example, bytreating the starting material with an alcohol, primarily with a loweralkanol, eg. methanol, ethanol, propanol, n-butanol, isobutanol and thelike, or a substituted lower alkanol. The reaction may be carried out inthe presence of a Lewis base, such as, for example, an alkoxide ion, as,for example, furnished by an alkali metal lalcoholate, especially analkali metal lower alkanol-ate, cg. lithium, sodium or potassiummethanolate, ethanolate, n-propanolate, n-butanolate, isobutanolate andthe like, an alkaline earth metal lower alk-anolate, e. g. barium orstrontium methanolate, ethanolate, n-propanolate, n butanolate,isobutanolate and the like, or an aluminum lower alkanolate, erg.aluminum methanolate, ethanolate, n-propanolate, isopropanolate,n-buta-nolate, isobutanolate and the like. The individual alcoholatecompounds are employed together with the corresponding alcohol used asthe transesterification reagent. Other alcohols, such as substitutedlower alk-anols, may be used in the presence of the corresponding alkalimetal, alkaline earth metal or aluminum .alcoholates. Other Lewisbase-type catalysts are, for example, an alkali metal cyanide, e.g.potassium cyanide and the like, a strong quaternary ammonium hydroxide,e.g. benzyl-tri-methyl-ammonium hydroxide and the like, or any othersuitable transesterification catalyst. The transesterificat-i-onreaction may also be catalyzed by an acidic reagent; an inorganic acid,such as tungstic acid and the like, or an organic acid, such asp-toluene sulfonic acids and the like, may be employed.

Apart from the esterifying alcohol, which may simultaneously serve as adiluent, other inert solvents may be used in the above-mentionedtransesterification reaction; carbocyclic aryl hydrocarbons, e.g.benzene, toluene and the like, are examples of such inert solvents. Ifnecessary, the reaction may be carried out at an elevated temperature,under increased pressure and/or in the atmosphere of an inert gas, e.g.nitrogen.

Conversion of a IGB-esterificd carboxyl group into anotherlofi-esterified carboxyl group may also be achieved by hydrolysis andsubsequently re-esterification of the free l6[3-canboxyl group in aresulting 3-epi-allo-yohimban-lS-one l6fl-canboxyl-ic acid.

Hydrolysis of the l6/3-es-terifi-ed carboxyl group may be carried outaccording to known methods; for example, the esterified carboxyl groupmay be cleaved by treatment with an alkali metal hydroxide, e.g. sodiumhydroxide, potassium hydroxide and the like, in a lower alkanol, e.g.methanol, ethanol and the like, or, preferably, in an aqueous solutionof a lower alloanol.

The 16fi-carboxyl group in a resulting 3epi-alloyohimban-l8-oneIGB-carboxylic acid may be esterified according to known methods; forexample, the starting material, preferably a solution thereof, may betreated with a lower diazo-alkane or with a substituted lowerdiazo-alkane. The rdiazo-reagent, which is preferably used in the formof a solution thereof in an inert solvent, may be added to the startingmaterial or a solution thereof; suitable solvents are, for example,ethers, e.g. diethylether, tetrahydrofuran and the like, loweralk-anols, e.g. methanol, ethanol and the like, halogenatedhydrocarbons, e.g. chloroform, methyleneohlor-ide and the like, or anyother appropriate solvents. An excess of the diazo compound presentafter the completion of the reaction may be destroyed, for example, byadding an additional carboxylic acid, such as acetic, benzoic acid andthe like. a

The compounds of the present invention, as well as the startingmaterials and inter-mediates used in their formation, or derivativesthereof, may be present in the form of mixtures of racemates, singleracenrates or antipodes.

Mixtures 'of racemates of final products or starting materials may beseparated into the single racemate-s on the basis of physico-chemicaldifferences, for example, by fractionated crystallization and the like.

Racemates of intermediates and final products may be resolved intoantipodes, for example, by treating 'a solution of the free racemic basein a suitable inert solvent with one of the optically active forms of anacid having an asymmetric carbon atom, or a solution thereof. Especiallyuseful as opticallyy active forms of salt-forming acids having anasymmetric carbon atom are D- and L-tartaric acid, as well as theoptically active forms of di-o-toluyl-tartaric, malic, mandelic,camPhor-lO-sulfonic,

quinic acid and the like. A salt may then be isolated, which is formedby the optically active acid with one of the optically active forms ofthe base. From a resulting salt, the free and optically active compoundsmay be obtained according to known methods used for the conversion of asalt into a free compound, for example, as outlined hereinbefore; aresulting optically active base may be converted into a functionalketonic derivative or into an acid addition salt, an N-oxide or an acidaddition salt of an N-oxide thereof according to the previouslydescribed procedure. The optically active forms may also be obtained byresolution with biochemical methods.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining step(s) of the process is(are) carried out. It also includes any new intermediates, which may beformed in one of the procedures outlined hereinbefore.

In the process of this invention such starting materiials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

This is a continuation-in-part application of our application Serial No.66,691, filed November 2, 1960, now abandoned.

The following examples illustrate the invention and are not to beconstrued as being limitations thereon. Temperatures are given indegrees centigrade.

Example 1 A mixture of 3.17 g. of methyl18-O-(4-bromophenylsulfonyl)-reserpate, 0.6 g. of N,N,N-triethylamineand 15 ml. of dimethyl sulfoxide is heated at 100 over a period of threehours while stirring. The cooled solution is poured into 100 ml. of acold, approximately four percent aqueous solution of sodium carbonate,the resulting precipitate is filtered oil and the solid material isdissolved in methylene chloride. The organic solution is washed withdilute aqueous sodium carbonate and then with saturated aqueous sodiumchloride solution, dried and evaporated. The residue is triturated withdiethyl ether, the crystalline material is filtered off and washed withdiethyl ether to yield 1.5 g. of methyl 185- desoxy-lS-oxo-reserpate ofthe formula:

which melts at 240-241 (decomposition) after several recrystallizationsfrom 95 percent ethanol; [a] =l7 (in chloroform).

The starting material used in the above reaction may be prepared asfollows: To a solution of 10.0 g. of methyl reserpate in 70 ml. ofpyridine is added 15.8 g. of 4- bromo-benzene sulfonyl chloride; thereaction mixture is allowed to stand at room temperature for 2 /2 daysand is then poured into ice-water. The organic material is extractedwith chloroform, the organic extract is washed with a 5 percent aqueoussodium hydroxide solution and subsequently with water until a neutralreaction is obtained. The organic solution is evaporated to dryness, andthe resulting methyl 18-0-(4-bromo-phenyl-sulfonyl) reserpate isrecrystallized from acetone, M.P. 209-212; yield: 5.64 g.

Selecting the appropriate starting materials, other 3-epi-allo-yohimban-l8-one 16,8-carboxylic acid esters, such as, forexample, other lower alkyl l8fi-desoxy-l8-oxoreserpates, e.g.

ethyl 18(3-desoxy-18-oxo-reserpate,

n-propyl l8fi-desoxy-18-oxo-reserpate,

isopropyl 18(3-desoxy-18-oXo-reserpate,

n-butyl 18fl-desoxy-18-oxo-reserpate,

isobutyl 18B-desoxy-18-oxo-reserpate,

n-pentyl 18/3-desoxy-l 8-oxo-reserpate,

n-hexyl 18/3-desoXy-18-oxoreserpate and the like,

lower alkyl 18,8-des'oxy-9-methoXy-18-oXo-deserpidates,

methyl l8B-desoxy-9-methoxy-18-oxo-deserpidate,

ethyl 18B-desoxy-9-methoxy-1 8-oxo-deserpidate,

n-propyl 18 B-desoxy-9-methoxy-1 8-oxo-deserpidate and the like,

lower alkyl l8/3-desoxy- 1 O-methoxy- 1 8-oxodeserpidates,

e.g. methyl 8,8-desoxy-10-methoxy-8-oxo-deserpidate, ethyll8fi-desoxy-IO-methoxy-l8 oxo-deserpidate, n-propyl18fl-desoxy-10-methoxy-18-oxo-deserpidate, isopropyl18fi-desoxy-l0-methoxy-18-oXo-deserpidate and the like, lower alkyl18fi-desoxy-10-ethoxy-l8-oxo-deserpidates,

methyl 18fi-desoxy-10-ethoxy-18-oxo-deserpidate,

ethyl 18fi-desoxy-IO-ethoxy-l8-oxo-deserpidate and the like,

lower alkyl 18,3-desoxy-1l-ethoxy-18-oxo-deserpidates,

methyl 18 B-desoxy-l l-ethoxy- 1 8-oxo-deserpidate,

ethyl l8fi-desoxy-1l-ethoxy-l8-oxo-deserpidate and the like,

lower alkyl 18/3-des0xy-18-oXo-ll-n-propyloxy-deserpidates, e.g.

methyl 18 B-desoxyl 8-oXo-1 l-n-propyloxy-deserpidate,

ethyl 18,6-desoxy-18-oxo-1l-n-propyloxy-deserpidate and the like,

lower alkyl 18,6-desoxy-1l-isopropyloxy-l8-oxo-deserpidates, e.g.

methyl 1 8 fi-desoxy- 1 l-isopropyloxy-l 8-oxo-deserpidate,

ethyl 18,6-desoxy-1l-isopropyloxy-l8-oxo-deserpidate and the like,

lower alkyl 1l-n-butyloxy-l8/3-desoxy-l8-oxo-deserpidates, e.g.

methyl ll-n-butyl-oxo-l8,8-desoxy-18-oxo-deserpidate,

ethyl 1l-n-butyloxy-l8fi-desoxy-l8-oxo-deserpidate and the like,

lower alkyl l8fl-desoxy-12-methoxy-18-oxo-deserpidates,

3-N,N-dimethylarninopropyl 1 8 ,B-desoxyl 8-oxo-reserpate and the like,

N,N-di-lower alkyl-amino-lower alkyl-18-oXo-deserpidates, e.g.

Z-N,N-dimethylaminoethyl 1 8 desoxy-l 8-oXo-deserpidate,

2-N,N-diethylarninoethyl lSfl-desoxy-l8-oXo-deserpidate,

2-N,N-dimethylaminopropyl l8B-desoXy-18-oxo-deserpidate and the like,

are prepared according to the above-described procedure.

Example 2 To a solution of methyl 1SB-desoxy-l8-oxo-reserpate in acetoneis added a solution of an equivalent amount of concentrated hydrochloricacid. On scratching, the desired methyl 18fi-desoxy-18-oxo-reserpatehydrochloride crystallizes as the monohydrate, M.P. 229-233 (withdecomposition).

. Example 3 To a warm solution of 0.41 g. of methyl l8li-desoxy18-oX0-reserpate in about -15 ml. of acetone is added a solution of 0.12g, of maleic acid in acetone; the desired methyll8B-desoXy-18-oXo-reserpate maleate hemihydrate melts at 189191 (withdecomposition).

Example 4 A mixture of 2.06 g. of methyl l8fi-desoxy-l8-oxo reserpate,2.0 g. of hydroxylamine hydrochloride, 50 ml. of anhydrous pyridine and50 ml. of absolute ethanol is refluxed for 3 /2 hours. The solvent isevaporated under reduced pressure, the residue is dissolved in water,the solution is made alkaline with aqueous ammonia, and the supernatantsolution is decanted from the gummy material. Water is added, and themixture is stirred and separated by filtration. The granular material iswashed with water and recrystallized from about 20 ml. of methanol byadding methylene chloride to the boiling slurry and then evaporating themethylene chloride. The analytically pure methyl18,8-desoXy-l8-oXin1ino-reserpate of the formula:

melts at 236-237".

Other l8-oXimino-3-epi-allo-yohimbane l6,8carboxylic acid esters, suchas other lower alkyl 18B-desoxy-l8- oXimino-reserpates, e.g.

ethyl 1SB-desoxy-l8-oximino-reserpate,

n-propyl ISfl-desoxy- 1 8-oXimin0-reserp ate,

isopropyl 18,8-desoXy-18-oXimino-reserpate,

n-butyl 18,8-desoxy-18-oXimino-resperate,

isobutyl 185-desoxy-18-oximino-reserpate,

n-pentyl 18/3-desoxy-l8-oximino-reserpate,

n-hexyl l8fi-desoxy-1S-oximino-reserpate and the like,

lower alkyl 1813-desoxy-9-methoxy-18-oximinodeserpidates, e.g.

methyl 18fl-desoxy-9-methoxy-18-oXimino-deserpidate,

ethyl l8fi-desoxyl O-methoxyl 8-oximino-deserpidate,

n-propyl 18f3-desoXy-9-methoxy-18-oXimino-desperpidate and the like,

lower alkyl 1SB-desoxy-IO-methoxy-lS-oximinodeserpidates, e.g.

methyl 1 8,8-desoxy-10-methoxy-l 8-oXimino-deserpidate,

ethyl 18fi-desoxyl O-methoxy- 1 8-oximinio-deserpidate,

n-propyl 18,8-desoxy-l0-methoxy-l8-oXimino-deserpidate,

isopropyl lSB-desoxy-IO-methoxy-l8-oximino-deserpidate and the like,

lower alkyl 18B-des0xy-10-ethoxy-l8-oximino deserpidates, e.g.

methyl 18,8-des0xyl O-ethoxy- 1 8-oximino-deserpidate,

ethyl 18B-desoxy-l0-ethoxy-l8-oXimino-deserpidate and the like,

lower alkyl lSfi-desoxy-ll-ethoxy-lS-oximinodeserpidates, e.g.

methy 18,8-desoxy-1l-ethoxy-l8-oximino-deserpidate,

ethyl lSB-desoxy-ll-ethoxy-l8-oximino-deserpidate and the like,

lower alkyl l8fl-desoXy-18-oximino-1l-n-propyloxydeserpidates, e.g.

methyl 18fi-desoxy-18-0ximino-l l-n-propyloxy-deserpidate,

ethyl 18B-desoxy l8-oximino-ll-n-propyloxy-l8-oxodeserpidate and thelike,

lower alkyl -desoxy-ll-isoproplyoxy-l8-oximinodeserpidates, e.g.

methyl 18fi-d6SOXY-1 l-isopropyloxy-l 8-oximinodeserpidate,

ethyl ISB-desoxy-l l-isopropyloxy-l8-oXimino-deserpidate and the like,

lower alkyl 1l-n-butyloxy-18,8-desoxy-18-oxirninodeserpidates, e.g.

methyl 1 l-n-butyloxyl 8/3-desoxyl 8-oximino-deserpidate,

ethyl 1 l-n-butyloXy-l8B-desoxy-18-oximino-deserpidate and the like,

lower alkyl l8fl-desoxy-l2-methoXy-l8-oximinodeserpidates, e.g.

18fi-desoxy-12-methoXy-l8-oXimino-deserpidate,

ethyl l8/8-desoxy-12-methoxy-18-oximino-deserpidate and the like,

lower alkyl 18,8-desoxy-l8-oximino-deserpidates, e.g.

methyl l8,8-desoxy-l8-oximino-deserpidate,

n-propyl lSfl-desoxy-l8-oXimino-deserpidate,

isopropyl 18,6-desoxy-18-oximino-deserpidate,

n-butyl l8fi-desoxy-18-oXimino-deserpidate,

is obutyl 1SB-desoxy-l8-oXimino-deserpidate,

secondary butyl 18a-desoxy-18-oximino-deserpidate,

n-pentyl l8fl-desoxy-l8-oXimino-deserpidate and the like,

or other esters of l8/3-desoxy-l8-oXimino-deserpidic acids,

such as, for example, lower alkyl 5-methyl-l8p-desoxy-18-oXimino-reserpates,

lower alkyl l8p-disoxy-6-rnethyl-l8-oximino-reserpates,

lower alkyl 18fl-desoXy-18-oXimino-reserpates,

lower alkyl 18fl-desoxy-6-methyl-l8-oXimino-deserpidates,

lower alkyl l8B-desoxy-9-methyl-18-oximino-desperpidates,

lower alkyl 1SB-desoxy-10-methyl-l8-oximinodeserpidates,

lower alkyl ISB-desoxy-l l-methyl-lS-oximinodeserpidates,

lower alkyl l8,8-desoXy-l0-methoXy-18-oximinoreserpates,

lower alkyl l8fl-desoXy-9,10-dimethoxy-18-oximinoreserpates,

lower alkyl 18,B-clesoxy-10,ll-methylenedioxy-l8-oximinodeserpidates,

lower alkyl 10-benzyloxy-l8p-desoxy-18-oximinodeserpidates,

lower alkyl 1l-benzyloxy-lSB-desoxy-l8-oximinodeserpidates,

lower alkyl 1Spt-desoxyIO-methylmercapto-18-oximinodeserpidates,

lower alkyl 18,8-desoXy-1l-methylmercapto-l8-oximinodeserpidates,

lower alkyl 18,8-desoxy-ll-ethylmercapto-l8-oxin1inodeserpidates,

lower alkyl 18fl-desoXy-1l-fluoro-l8-oxirnino-deserpidates,

lower alkyl 1-O-chloro-18/3-desoXy-l8-oximinodeserpidates,

lower alkyl '18fl-desoxy-9,l2-dichloro-l8-oximinodeserpidates,

lower alkyl 18,8-desoxy-1 1,12-dichloro-1 8-oximinodeserpidates,

lower alkyl 18,8-desoxy-10-bromo-l8-oximino-reserpates,

lower alkyl 18B-desoxy-11-N,Nedimethylamino-18- -oximino-deserpidates,

lower alkyl :l7a-desmethoxy l8 3-desoxy-l7u-ethoxy l 8-oximino-reserpates,

lower alkyl17a-desmethoxy-18fi-desoxy-18-oximino-17an-propyloxy-reserpates,

lower alkyl17a-desmethoxy-l8fl-desoxy-l7a-isopropyloxy-l8-oximino-reserpates,

lower alkyl 17a-desmethoxy-18 8-desoxy-l7u-ethoxy-l8-oximino-deserpidates,

lower alkyl 17a-cyano-l7u-desmethoxy-l8B-desoxy-l8- oximino-reserpates,

lower alkyl Hot-cyano-17a-desmethoxy-1-8B desoxy-l8-oximino-deserpidates,

lower alkoxy-lower alkyl l8fl-desoxy-18-oximinoreserpates,

lower alkoxy-lower alkyl 18fl-desoxy-18-oximinodeserpidates,

N,N-di-lower alkyl-amino-lower alkyl 1813-desoxy-18- oximino-reserpates,

N,N-di-1ow-er alkyl-amino-lower alkyl l8-oximinodeserpidates and thelike,

may be prepared according to the previously described procedure, usingthe previously described 3-epi-allo-yohimban-lS-one l6fl-carboxylic acidesters as starting materials.

Example 5 To a suspension of 043 g. of methyl 18fi-desoxy--l8-oximino-reserpate in 5 ml. of methanol is added a :solution of 0.1 ml.of concentrated hydrochloric acid in 1 ml. of methanol. Completesolution occurs on stirring, and

on scratching, crystallization sets in. The solid material is filteredoff, washed with cold methanol and recrystallized from methanol to yieldthe methyl 18fl-desoxy-l8- oximino-reserpate hydrochloride monohydrate,239 (with decomposition).

Example 6 is recrystallized from methanol, M.P. 196-201";

[ lD =-|-58.5 (in chloroform).

To a solution of 0.61 .g. of methyl .1'8B-desoxy-l8-oxoreserpatesemicarbazon'e in 30 of acetone i's'a'dded a solution of 0.13 ml. ofconcentrated hydrochloric acid in 1.5 m1. of acetone. The reactionmixture is chilled, the resulting precipitate is filtered oil and washedwith acetone. The methyl 18fl-desoxy-l8-0xo=reserpate semicarbazonehydrochloride sesquihydrate, after drying at room temperature overphosphorus pentoxide, starts to decompose at about 245.

Example 7 A mixture of 0.41 g. of methyl 18B-desoxy-l8-oxoreserp'ate,0.6 ml. of ethylene :glycol and 0.2 g. of ptoluene sulfonic acidin ml.of dry ethylene dichloride is refluxed in a 'Soxhlet apparatus in suchmanner that the condensate passes through the thimble containing .anhy-.drous calcium sulfate; the reaction, which is maintained for six hours,is carried out in a nitrogen atmosphere. The solution is then washedtwice with a '5 ,percent aqueous solution of sodium carbonate, twicewith water and once with asaturated-aqueowssodium chloride solution,dried over sodium sulfate and then evaporated .to dryness. The residueis triturated with diethyl ether to yield the crystalline methyl-18fi-desoxy-l8-ethylenedioxy .resenpate of the formula:

which is recrystallized from a mixture of benzene and cyclohexane, M.P.205-2062 '[a] =-56 (in chloroform).

Example 8 To a suspension 015 0.82 g. of methyl l8p-desoxy-l8-oxo-reserpate in 35 m1. of methanol is added 0.8 g. of sodiumborohydride. The mixture is allowed to stand for one-half hour, duringwhich time the initially vigorous reaction subsides. The solvent is thenevaporated under reduced pressure, ice-water is added to the residue andthe resulting solid is filtered off, is washed with water and dried. Tworecrystallizations from acetonitrile yield 0.43 g. of methyl18-epi-reserpate monohydrate, which melts at 22l-223 (decomposition) Thecrystalline material resulting by twice recrystallizing the residue ofthe mother liquors obtained after the first of the two aboverecrystallizations from acetonitrile yields methyl reseipate, M.P.242-244.

The above methyl lS-epi-restsrpate, when treated with an organicsulfonic acid halide, such as, for example, 4- bromo-benzene sulfonylchloride, S-nitro-benzene sulfonyl chloride and the like, preferably inthe presence of pyridine, yields a methyl 18-epi-O-(organicsulfonyl)-reserpate, e.g. the methyl l8-epi-O-(4-bromo-phenyl-su1fonyl)-reserpate (M.P. 2102l2), methyll8-epi-O-(3-nitrophenyl-sulfonyD-reserpate (M.P. 174176) and the like,which upon treatment with a lower alkanol, e.g. methanol, ethanol, npropanol and the like, if necessary, in the presence of a base, e.g.N,N,Ntriethylamine, pyridine and the like, yields a methyl 18-O-loweralkyl-reserpate, e.g. methyl IS-O-methyl-reserpate (M.P. 235-237),methyl 18-O-ethyl-resenpate (M.P. 22l-222.5) and the like. The lattercompounds have strong sedative and tranquilizing effects.

19 What is claimed is: 1. A member selected from the group consisting ofa compound of the formula:

in which R is a member selected from the group consisting of loweralkyl, phenyl-lower alkyl, lower alkoxylower alkyl, in which lower alkylseparates lower alkoxy from the carboxyl group by two to four carbonatoms, and N,N-di-lower alkyl-amino-lower alkyl, in which lower alkylseparates N,N-di-lower alkyl-amino from the carboxyl group by two tofour carbon atoms, R stands for a member selected from the groupconsisting of lower alkoxy and cyano, each of the groups R R and R is amember selected from the group consisting of hydrogen, lower alkyl,lower alkoxy, phenyl-lower alkoxy, halogeno, lower alkyl-mercapto, and,whenever two of the groups R R and R are attached to two adjacentpositions and taken together, lower alkylenedioxy, and R is a memberselected from the group consisting of hydrogen and lower alkyl, an oximeof such compound, a semicarbazone of such compound and a lower alkyleneglycol ketal of such compound, and a non-toxic acid addition saltthereof, an N-oxide thereof and a non-toxic acid addition salt of anN-oxide thereof.

2. A member selected from the group consisting of a compound of theformula:

in which R is lower alkyl and R is lower alkoxy, and a non-toxic acidaddition salt thereof.

9. Lower alkyl 18,8-desoxy-18-oXimino-reserpate.

10. A non-toxic acid addition salt of lower alkyl18pdesoxy-l8-oximino-reserpate.

11. Methyl 18fi-desoxy-18-oXimino-reserpate.

12. Methyl 18,9 desoxy 18 oximino reserpate hydrochloride.

References Cited in the file of this patent Kornblum et al.: Jour. Amer.Chem. Soc., vol. 79 (1957), page 6562.

Kornblum et al.: Jour. Amer. Chem. Soc., vol. 81 '(1959), pages 4113 and4114.

Hunsberger et al.: Chemistry and Industry (1959), page 88.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA: